Which antithrombotic strategy provides the best outcomes after mitral valve repair in patients who remain in sinus rhythm?

Summary A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was ‘in the first 3-months after mitral valve repair (MVRep) which antiplatelet and/or anticoagulant strategy should be instigated in patients who remain in normal sinus rhythm’. Altogether 77 papers were found using the reported search, of which 8 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude that there remains a lack of high-quality randomized studies, controlling for postoperative cardiac rhythm, comparing vitamin K antagonists (VKA) and antiplatelet therapy in the early postoperative period following isolated MVRep. Current guidelines are based on limited evidence or expert consensus alone. Based on the currently available evidence, the authors conclude that antiplatelet therapy (e.g. aspirin) is safe and appropriate to use in the 3-month postoperative period following isolated MVRep, in those without preoperative, or postoperative atrial fibrillation. Rates of thromboembolic events are comparable between these patient groups (i.e. VKA versus aspirin), whilst VKA therapy is associated with increased rates of major bleeding events and mortality.


INTRODUCTION
A best evidence topic was constructed according to a structured protocol. This is fully described in the ICVTS [1].

THREE-PART QUESTION
In patients undergoing [mitral valve repair] which [anticoagulation and/or antiplatelet strategy] provides [the best outcomes in the first three post-operative months].

CLINICAL SCENARIO
A 70-year-old patient, with a history of hypertension, is consented for mitral valve repair (MVRep) due to a degenerative mitral regurgitation. The procedure is uneventful, and the patient remains in sinus rhythm throughout the admission. You know that there is a particularly increased risk of thromboembolic events in the first 3 months following MVRep due to ongoing endothelialization of the prosthetic material. The patient has no background of AF preoperatively, however you recognize the increased incidence of postoperative new-onset AF within this patient group. You liaise with your colleagues within the department, who give varying strategies for thromboembolic prophylaxis in this patient group. Consequently, you search for what the best short-term postoperative antiplatelet/anticoagulant strategy would be for this patient according to the best evidence.

SEARCH OUTCOME
A total of 77 papers were found using the reported search. From these, 8 papers were identified that provided the best evidence to answer the question. These are presented in Table 1.

RESULTS
This best evidence topic acts as an update to that by Asopa et al. [2] and looks to provide a renewal of the best evidence following its publication. The authors concluded that 3 months of anticoagulation should remain the standard of care following MVRep, due to the paucity of high-quality evidence supporting the safety of omitting warfarin, together with high rates of AF following discharge [2]. Current guidelines within the area provide mixed recommendations, typically based upon weak evidence or expert consensus. The 2012 American College of Chest Physicians Guidelines recommend antiplatelet therapy for the first 3 months over a VKA, in those patients undergoing MVRep with a prosthetic ring and in normal sinus rhythm [3]. Conversely, the 2021 European Society of Cardiology/European Association for Cardio-Thoracic Surgery (EACTS) make a class IIa recommendation that oral anticoagulation should be considered for the first 3 months after MVRep, regardless of cardiac rhythm, based upon level C evidence [4]. Despite the comparable risk of thromboembolism with aspirin and VKA following MVRep, the high incidence of newonset AF and resistance to aspirin makes VKAs the preferable option, in view of the lack of randomized data [4]. This recommendation is supported by the previous 2017 EACTS guideline on 'perioperative medication in adult cardiac surgery' [5]. The preceding 2008 EACTS recommendations by Dunning et al. concluded that patients with indications for anticoagulation (e.g. AF) should be anticoagulated, whereas those without such risk factors may benefit from anticoagulation or antiplatelet therapy alone [6]. Similarly, the 2014 guidance published by American Heart Association/American College of Cardiology gave a class IIa recommendation for the utilization of a VKA in the first 3 months following MVRep, or lifelong in those with risk factors (e.g. AF, previous thromboembolism or hypercoagulable condition) to achieve an international normalized ratio (INR) of 2.5 (range 2.0-3.0), also based upon level C evidence [7]. The more recent 2020 guideline from the American College of Cardiology/American Heart Association provides no formal update to the aforementioned; stating that the beneficial effects seen with antiplatelet agents in bioprosthetic aortic valves may apply to mitral valves, in the context of MVRep. It should be noted that many of the aforementioned guidelines base their recommendations on nonrandomized observational studies for aortic bioprosthesis, and not from the literature following MVRep.
Similarly, van der Wall et al. [9] in a multicentre, retrospective observational cohort study (n = 469) evaluated thromboembolic and bleeding events between patients receiving VKA (target INR 2.0-3.0) (n = 325) or aspirin (n = 144) (80 mg once daily) in the 3 months following MVRep. They excluded those undergoing concomitant cardiac surgery, or with preoperative AF. Cases of new-onset postoperative AF for >24 h were commenced on low molecular weight heparin and bridged onto VKA if originally receiving aspirin. MVRep involved the implantation of an annuloplasty ring and a variety of concomitant techniques (e.g. leaflet resections, artificial chords tendinae implant, chordal transposition or edge-to-edge technique)-the authors do not provide further details, nor adjusted/sub-analysis. Composite incidences combining thromboembolic and bleeding events were compared as a primary end point. In those without new-onset AF, the cumulative incidence of the primary end point occurred in 8.2% and 8.1% of those receiving VKA and aspirin, respectively (adjusted hazard ratio (HR) 0.97, 95% CI 0.32-2.9). When individually compared, thromboembolism [2.6% (VKA) vs 1.6% (aspirin), HR 0.82, 95% CI 0.16-4.2] and bleeding [6.8% (VKA) vs 9.1 (aspirin), HR 1.89, 95% CI 0.90-3.9] demonstrated no significant difference in incidences between the groups. Importantly, this secondary end point analysis did not adjust for new-onset postoperative AF (n = 220, (47%)).
Meurin et al. [10], in a prospective, non-randomized, multicentre study of 350 patients undergoing MVRep, looked to report the incidence of thromboembolic complications between groups receiving either VKA (target INR 2.0-3.0), aspirin (75-360 mg/day), VKA and aspirin, or no antithrombotic therapy. Their primary aim was to report the incidence of thromboembolic events in the early period (up to 6 weeks) after MVRep. Repair type was reported by the authors according to the Carpentier classification, with the prosthetic ring being used in all patients. Multivariate was not performed as factors such as Carpentier class, left-ventricular ejection fraction, age and permanent AF were not predicative of thromboembolism. Subgroup analysis was performed to report incidences in patients who remained in sinus rhythm, and without concomitant surgery (n = 185). They reported significantly increased rates of thromboembolic events in those not receiving any form of antithrombotic therapy (22%, n = 4) when compared to both VKA (3.5%, n = 4) and aspirin (0%) individually (P < 0.01). Whereas there was no significant difference in the incidence of thromboembolism between the VKA and aspirin groups (P = 0.15). Overall, they concluded that the lack of antithrombotic therapy in any form is a predictive factor for thromboembolic events.
The retrospective nature of all the studies within this field, along with the low numbers of patients included, results in numerous limitations and varying degrees of selection bias. Namely, there is a lack of control for surgeon-specific preferences, temporal trends in prescribing practice and adjustment for the type of repair performed. As such, studies and data are lacking in the best practice for those who remain in sinus rhythm following discharge; in addition, the role of novel-oral anticoagulants in those who develop atrial fibrillation remains unexplored.